BELITE BIO / 1

Blindness & Liver Fibrosis

Feb 2019

RBP4 Technologyfor Anti-Aging

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PLATFORM OVERVIEW

Anti-RBP4 PlatformTherapies for Aging Metabolic Diseases

RBP4 protein transports retinol (vitamin A) from the liver to peripheral tissues. It is:

Highly Expressedin the liver and adipose tissue

Easily Measuredvia blood samples (ELISA)

Linked to Aging Metabolic DiseasesEvidence linking elevated RBP4 to diabetes, liver disease and macular degeneration

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Anti-RBP4 Platform for Aging Metabolic Diseases

MEET THE UNMET NEED

HOPE TO INCURABLE BLINDNESS

THE PATH TO METABOLIC DISEASE

Dry Age-Related Macular Degeneration & Stargardt Disease

Non-Alcoholic Fatty Liver Disease & Type 2 Diabetes

009LBS

PRE-CL IN ICAL

PHASE I

008LBS

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For Dry Age-Related Macular Degeneration & Stargardt DiseaseHOPE TO INCURABLE BLINDESS

10M

$20B170M

Blind victims suffer from macular degeneration in the US

Cases of AMD worldwide with a global direct healthcare cost of USD 255B

Estimated global market size

1 in 10,000Stargardt Disease Juvenile onset macular degeneration (rare pediatric disease & orphan disease)

MARKETKEY OPPORTUNITY

Zero ApprovedTreatments

DISCOVERY

PRE-CLINICAL

PHASE I

PHASE II / III

MARKET

LBS

008

RPD ODDfor Stargardt (US & EU)

Most Advanced Candidate

Reference: Globaldata, Lancet, Orphanet, STEM CELLS Translational Medicine

NIH Blueprint

L B S

008

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Symptoms of AMDPRODUCT DISEASE PROFILE

NormalCentral Vision

Blurry &DistortedCentral Vision

LostCentral Vision

Normal Macula

Early Dry AMDLipofuscin accumulation

Drusen formationand inflammation

Late Stage Geographic Atrophy

L B S

008

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Pathogenesis of AMD & Stargardt DiseasePRODUCT DISEASE PROFILE: 90% AMD ARE “DRY” AMD

Normal Retina RPE Changes Rods Die, Cones Spared Cones Die

Vision Loss

L B S

008

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MOA: Dry AMD & StargardtRBP4 Transports Retinol (Precursor to Ccytotoxic A2E) into Retina by Way of Visual Cycle

PHOTORECEPTORS(PR)

RETINAL PIGMENT EPITHELIUM (RPE)

BLOODSTREAMLBS-008 RBP4Inhibits RBP4 from delivering retinol into RPE, reducing A2E accumulation by 50%

Primary transporter of retinol into RPE

Loss of RPE

A2E

RPE65 LRAT

11c-RDHat-RDH

at-Ral

at-RE at-Rol11c-Rol

Retinal isomers are required by normal visual function. They are also precursors to the cytotoxic

A2E, which causes dry AMD and Stargardt.

Rhodopsin

LBS-008 Induced Down-Regulation

Retinal Isomers

Enzymes

Pigments

ABCA4

DRY AMD

Loss of PR, ERG abnormalities

STARGARDT11c-Ral

Gene mutation causes loss of

ABCA4 transporter

function

STARGARDT

L B S

008

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Reduces Bisretinoid Accumulation by 80%IN ABCA4-/-RDH8-/- MICE, COMPARED TO LBS-008-TREATED

1.75

26

6

56

48

3

p=0.003; unpaired t-test

Wild Type untreated control

DKOvehicle-treated control

DKOLBS-008-treated

Serum RBP4(ug/mL)

A2E Concentration(pmol per eye)

L B S

008

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Degeneration in Abca4-/-Rdh8-/- Mice

0

10

20

30

40

50

60

70

ON

L th

ickn

ess

(μ

m)

inferior Distance from ONH superior

C57BL/6J DKO, untreated DKO, BPN14967-treated

Dry AMD or Stargardt’s is associated with

thinning of the outer nuclear layer (ONL)

and the loss of photoreceptor cells,

indicating macular degeneration.

We quantified the ONL thickness and found ONL

thickness was significantly decreased in the diseased

group (abcd4/rdh8 knockout mice), as compared to

the diseased group treated with LBS-008, ONL were

preserved, which implies the treatment group has not

loss photoreceptor cells.

IN ABCA4-/-RDH8-/- MICE, COMPARED TO LBS-008-TREATED

LBS-008-

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008

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PRODUCT DISEASE PROFILE

“In the 300 mg fenretinide dose cohort…showed a trend for slowing of lesion growth, particularly among patients who had RBP and retinol levels reduced by more than 50%.”

Pharmacotherapy of AMD Chapter 67, Mark S. Bluemenkranz (2015)

“Patients in the 300mg treatment group who completed the 2-year studyachieved reductions of RBP4 <2mg/DL (1 uM) correlated with further reductions of lesion growth rate (a mean reduction of 0.33mm2 in yearly lesion growth).”

“Fenretinide treatment also reduced approx. 45% incidence of choroidal neovascularization (Wet AMD)”

Investigation Of Oral Fenretinide For Treatment Of Geographic Atrophy in Age-Related Macular Degeneration (Nathan L. Mata, PhD)

placebo

300 mg

Medium Lesion Growth (50%)

RBP Reduction (%, from baseline)

Le

sio

n I

ncr

ea

se(%

, fro

m b

ase

line

)

RBP4 Reduction Stops AMD Progression

L B S

008

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Robust Serum RBP4 ReductionMONKEY STUDY DATA: -5 mg/kg PO dose in non-human primates

Since LBS-008 reduces RBP4 in the

circulation and cleared from the kidney,

it can be easily measured in blood and

urine samples, and thus the amount of

retinol that gets into the visual cycle can

be predicted and easily controlled and

managed.

90% Reduction12h after single dose

70% Reduction36h after single dose

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DISCOVERY

PRE-CLINICAL

PHASE I

PHASE II / III

MARKET

LBS

009 For Non-Alcoholic Fatty Liver Disease & Type 2 DiabetesTHE PATH TO METABOLIC DISEASES

100M

$20B9M

Individuals with NAFLD in the US alone

30% of general population

NASH cases in the US alone

3% of general population

Addressable total global market size by 2026. Global market size for type 2 diabetes estimated to reach $59B by 2026

1.46BCases of NAFLD worldwide

20% of global population

MARKETKEY OPPORTUNITY

Zero ApprovedTreatmentsfor Non-Alcoholic Steatohepatitis (NASH)

Reference: NIH, Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease, Marketwatch, Globadata

L B S

009

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RBP4 Contributes to Diabetes & Liver DiseasePRODUCT DISEASE PROFILE

51.7

62.8

Normal(n=86)

NAFLD(n=73)

23.5

61

70.6

NGT(n=19)

IGT(n=20)

T2D(n=20)

35.1

46.9

53

Control(n=30)

T2D(n=30)

T2D + NAFLD

(n=30)

**

**

***

RB

P4

(ug

/mL)

P vs Normal P vs NGT

P vs Control

145 publications on RBP4 & Metabolic Syndrome

84 publications on RBP4 & Fatty Liver

“These findings suggest that this newly defined adipokinemight be related to pathogenesis of NAFLD.”

J A Seo et al. 2008Clin Endocrinol. 68(4) 555-560

“Iinsulin resistance is the strongest determinant of elvated serum RBP4 levels in IGT and T2D.”

Qin Yang et al. 2012Endocrinology. 153(3): 1519-1527

“These findings suggest that RBP4 might be related to pathogenesis of NAFLD.”

N A Ibrahim et al. 2016Int J Adv Res Biol Sci 3(4): 71-79

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009

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RBP4 is Strongly Associated with CHD RiskPRODUCT DISEASE PROFILE

“We found that full-length RBP4 levels were associated with a 3-fold increased risk

of incident CHD in women.”

Qi Sun et al. Circulation. 2013 May 14; 127(19): 1938–1947

Odds Ratio (95% CI) of CHD at 8 Years Since Baseline

Quartiles of Plasma RBP4 Levels (full length, μg/mL)

1

0.7

1.58

3.56

Q1 Q2 Q3 Q4

“… Visceral fat … secretes hormones and a host of other chemicals linked to diseases that commonly afflict

older adults. One such substance is called RBP4 that was found in a 16-year study of nurses to increase the

risk of developing coronary heart disease.”

New York Times, 2018 Jun 11

L B S

009

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Childhood RBP4 levels are strong predictors of developing Insulin Resistance and Metabolic Syndrome in Adults

PRODUCT DISEASE PROFILE

“high levels of childhood RBP4 at baseline were associated with an adverse

cardiovascular risk profile at baseline and upon 10 year follow-up”

Li et al. Cardiovasc Diabetol (2018) 17:69

“The most striking, novel finding of this study is that RBP4 levelsmeasured in childhood were strong predictors of the subsequent development of Metabolic Syndrome and each of its components

(including insulin resistant, hyperglycemia, hypertension and hyperlipidemia) 10 years later, and is independent of obesity.”

• 10-year prospective study in 3445 children• Participants with higher childhood RBP4 levels had adverse

cardiometabolic profiles at follow-up.• RBP4 is a reliable indicator of innate Insulin Resistance and its

ability to predict the onset and persistence of Metabolic Syndrome after 10-year follow-up

• After 10-year follow-up, baseline RBP4 (independent of BMI) predicted: o Blood Pressures elevation (P = 0.015)o Triglyceride elevation (P < 0.001)o Hyperglycemia (P = 0.009)o Insulin Resistance (P = 0.015)o Metabolic Syndrome (P = 0.002)

L B S

009

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RBP4 Also Found to Bind to Fatty AcidsPRODUCT DISEASE PROFILE

“We have shown that RBP4 is not specific for retinol but it is also found in plasma, urine and amniotic fluid bound to fatty acids.”

Massimiliano Perduca et al. Elsevier Data in Brief 18(2018). 1073-1081

RETINOL FATTY ACID

RBP4 side chains bound to RBP4 side chains bound to

L B S

009

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MOA Overview: RBP4 in Liver Disease & DiabetesRBP4 Causes Liver Inflammation & Insulin Resistance, Resulting in NASH & Diabetes

LBS-009 Induced Down-Regulation

APC activation+ inflammation

insulin resistance+ hypersecretion

LBS-009FREE FATTY ACIDS

TRIGLYERCIDES

NASHNon-Alcoholic SteatohepatitisLIVER

T2DType 2 DiabetesPANCREAS

Enlarged AdipocytesFAT

TISSUE

INSULIN INFLAMMATORY CYTOKINE SECRETION CD4 T CELL MACROPHAGE

RBP4

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009

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Robust Serum RBP4 Reduction ANIMAL STUDY DATA: -single 5 mg/kg PO dose in rats

85% Reduction10h after single dose

60% Reduction36h after single dose

L B S

009

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Decreased Liver Lipid Deposition in HFD Animals

Liver Histology Score Regular Diet +

VehicleHFD +

VehicleHFD +

LBS-009

regula

r die

t

HFD

HFD

+ C

om

pound

0

1

2

3

4

Liv

er h

isto

log

y s

co

re

****

****

***

Regular Diet

HFD HFD + LBS-009

Liv

er

His

tolo

gy S

core

RBP4 TRANSGENIC MICE ON HFD

0 2.9 1.6

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Blindness & Liver Fibrosis

contact@belitebio.com

RBP4 Technologyfor Anti-Aging